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Authors: ABSTRACT:
Waleed M. Al-Shaqha For a long time, several herbal medicines have been used for the treatment
of diabetes in the form of compound drugs. Moreover, after the references made by
Institution: researchers on diabetes mellitus, investigations on the hypoglycemic activity of
College of Medicine, compound drugs from medicinal plants have been more important. Although, the
Al-Imam Muhammad Ibn molecular mechanisms behind this effect is not much explored yet. There are various
Saud Islamic University
approaches to reduce the diabetes effect and its secondary complications, and herbal
(IMSIU), Riyadh-13317-
drugs are more preferred due to its less side effects and low cost. One of the major
7544, Kingdom of Saudi
Arabia (KSA). factors in the development of diabetes and its complications is the damage induced by
free radicals. Therefore antidiabetic compounds with antioxidant properties would be
more beneficial. It is hypothesized that the insulin mimetic effect, hypoglycemic effect
and -cell function of herbal remedies might add to glucose uptake through
improvement in the expression of genes of the glucose transporter (GLUT) family in
liver and skeletal muscles. Here we selected some plants with the ability to control
blood glucose as well as to modulate some of the mechanisms involved in insulin
resistance like -cell function, glucose transport (GLUT) gene and incretin related
pathways. Therefore, plants remedies may be appealing as an alternative and
adjunctive treatment for diabetes mellitus.
Keywords:
Herbal Remedies, Glucose Transporter (GLUT), mRNA.
neutralize free radicals, in reducing the effects of aging function has the ability to stabilize and reverse the
and cancer (Kubish et al., 1997; Naziroglu et al., 2001). detrimental effect of T2DM (Leahy et al., 2010;
These antioxidants also have the ability to prevent Ackermann et al., 2007).
experimentally induced diabetes in mouse models and Role of glucose transport gene (glut)
reduce diabetic complications. (Lipinski et al., 2001). Glucose is transported across the cell membrane
Mounting evidence from epidemiological studies by a family of integral membrane protein GLUT proteins
suggests that genetic and environmental factors are most that catalyzes facilitated diffusion of pentose and hexose
common causes for diabetes. Both factors contribute to sugar molecules down a concentration gradient. GLUT
become insulin resistance and loss of -cell function that protein contains 500 amino acids and share 25-68%
result in impairment in insulin action, insulin production, sequence identity with one another (Thorens and
or both. Mueckler, 2010). Nearly all the mammalian cells express
Nearly 5% of western population is affected by GLUTs and some of them help in the transport of
T2DM that is the most common endocrine disorder dehydroascorbate, urate or myoinositol apart from
(Zimmet et al., 2001; Shaw et al., 2010; Centers for glucose. Most cells express one isoform of GLUTs that
Disease Control and Prevention, US, 2011). Insulin is a helps in the transport of major monosaccharide unit
very important protein hormone that regulates the while other 13 isoforms are expressed at a lower level.
metabolism of fat, glucose and protein in cells. Patients Inhibition of GLUT-1-mediated sugar transport in human
with T2DM suffer from both reduced insulin secretion red cells by specific inhibitors reduces glucose
and inability to respond to insulin (Naziroglu et al., permeability by five orders of magnitude (Naftalin et al.,
2001). Insulin resistance has been attributed to elevated 1977). The GLUTs, therefore, provide a pathway for
levels of free fatty acids in plasma, (Zimmet et al., 2001) cellular sugar import across the cell membrane which is
leads to decreased glucose transport into muscle cells, otherwise a very effective barrier to trans-membrane
elevated, increased breakdown of fat and hepatic glucose flow of monosaccharaides. In most cells it is the glucose
production. Insulin is solely produced by pancreatic beta import which is the most important function because it is
cells and any defects in its production or mode of action a source of metabolic fuel, however, in some cells (liver,
results in grave metabolic consequences. Increased kidney and gastrointestinal tissues) export is required.
cardiovascular risk starts to appear much before the The major family of glucose transporters is the
development of hyperglycemia. Targeting beta cells GLUT gene family. The principal insulin-sensitive
early in the disease progression has resulted in a new glucose transporter in the liver and muscle is insulin-
approach to treat T2DM. (Boden et al., 1996). During the sensitive glucose transport gene (GLUT). Among the
induction of insulin resistance, such as is seen after large super family of transport facilitators GLUT genes
steroid administration, high-calorie diet, or physical form a subset and includes 12 SLC2A genes numbered 1
inactivity, increased glucagon levels and increased -12 encoding 12 GLUT proteins. GLUT1 is expressed
Glucose-dependent Insulinotropic Polypeptide (GIP) highly in erythrocytes and brain and GLUT2 is
levels accompany glucose intolerance; however, associated with Fanconi-Bickel syndrome. GLUT3 is
postprandial Glucagonlike Peptide-1 (GLP-1) response is responsible for glucose transport across neuronal plasma
unaltered (Tourrel et al., 2001). Several growth factors, membrane. Insulin regulated glucose transport in adipose
cell cycle mediators and nuclear factors regulate beta cell tissues, heart muscles and skeletal muscles are carried
homeostasis and maintaining and enhancing beta cells out by GLUT4. Skeletal muscles that are primary site for
Journal of Research in Biology (2015) 5(8):1885-1895 1887
Shaqha, 2015
dietary glucose disposal, metabolizes glucose via the application of science to health care in official
glycolysis and glycogen synthesis (Ikemoto et al., 1995). modern scientific medicine or allopathic. An anti-
GLUT4 regulation is also involved in obesity-induced diabetic herb with many phytochemicals may have
insulin resistance characterize by increased blood multiple benefits by targeting several metabolic
glucose and plasma insulin levels. GLUT4 mRNA and pathways. One study demonstrated that a combination
protein expression are reduced during adipose tissue therapy of modern medicine and herbal medicine
expansion which is another major site for dietary glucose exhibited a better (synergistic) effect than either
disposal and might represent an adaptive response in medicine alone (Kaur et al., 2012). Therefore, herbal
order to prevent brain against hypoglycemia (Garvey et medicines can be a complement of modern therapy in
al., 1991; Fronzo et al., 1985). GLUT5 is highly T2DM and provide hope for a cure. In our pervious study
expressed in intestine, testis, kidney, and GLUT7 we observed antidiabetic effect of catharanthus roseus
expression is currently unknown. GLUT5 and GLUT7 on STZ induced diabetes and comparison with
are present contiguously on chromosome 1p36.2 with a Metformin, treatment with c. roseus in diabetic wistar
high degree of sequence similarity (58% identical amino rats, the contents of glucose transport gene mRNA were
acids). GLUT5 is expressed in brain microglia though its restored to near normal values (Waleed et al., 2015).
function remains unclear (Kern et al., 1990; Slentz et al., All traditional medicines have their roots in
1992). Many studies indicate that glucose transport medicinal values and household remedies and play a
response to insulin in liver and skeletal muscle is heavily prominent role in human health care. WHO has listed
influenced by GLUTs. In fact one of the major reasons of 20,000 medicinal plants used in different parts of the
hyperglycemia is the decrease in glucose transport gene world, and among them, 1200 plants have been claimed
levels. Glucose unresponsiveness with GLUT gene to be anti-diabetes remedies (Marles and Farnsworth
impairment is a hallmark of T2DM and restoring GLUT 1995; Habeck 2003). Over 400 plants and 700 recipes
levels would enhance uptake of glucose in liver and help compounds have been scientifically evaluated for T2DM
combat hyperglycemia (Thorens et al., 1992). treatment (Singh et al. 2011). Metformin was developed
Herbal therapy for diabetes based on a biguanide compound from anti-diabetic herbs,
Throughout the human history people have relied French lilac, and is now a first line drug for T2DM
on natural products, particularly on plants. Medicinal (Oubre et al., 1997).
plants were applied to treat a wide range of disease Selected medicinal herbs for diabetes
categories (Basch et al., 2003) and maintain good health. More than 400 herbals and their compounds have
Past 200 years have witnessed not only an acceleration in shown anti-diabetic activities. Instead of listing 400
the rate of extinction of plant species but also in erosion herbals and their compounds, here, we selected some
of traditional knowledge related to the medicinal plants with the ability to control blood glucose as well as
properties and uses of herbal plants. Although herbal to modulate some of the mechanisms involved in insulin
medicine systems are sometimes misinterpreted as being resistance like -cell function, glucose transport (GLUT)
unscientific and anachronistic but their long-term gene and incretinrelated pathways.
existence proved that they are able to compete with Acacia arabica
modern medicine at some level. Therefore, use of Acacia arabica is a popular ornamental and
medicinal plants, mainly to distinguish the ancient and medicinal tree. Use of A. arabica for the prevention and
culture-bound health care practices, which existed before treatment of various health ailments has been in practice
for hundreds of years. The plant extract acts as an anti- glucose and lipids in serum and normalized the activities
diabetic agent by acting as secretagouge to release of liver hexokinase and glucose 6-phosphatase (Roman
insulin. It contains chiefly arabin which is the mixture of et al., 1995; Kumari et al., 1995). Scientific and
calcium, magnesium and potassium salts of arabic acid. pharmacological studies have found evidence that Allium
It induces hypoglycemia in control rats but not in cepa or their derived compounds have antimicrobial and
alloxanized animals. Powder of Acacia arabica, when antifungal properties, and may also be of benefit in
administered (2, 3 and 4 g/kg body weight) to normal preventing or treating heart disease and diabetes.
rabbits, induced a hypoglycemic effect by initiating the Allium sativum
release of insulin from pancreatic -cell (Wadood et al., Allium sativum is a strongly aromatic crop plant
1989). that has been cultivated for thousands of years, belonging
Aegle marmelos to the liliaceace. It has been used as a medicinal agent for
Aegle marmelos leaves (family of Rutaceae), thousands of years and is renowned throughout the world
which is also called as 61/va in ancient Sanskrit, has for its distinctive flavor and health-giving properties.
been used as herbal drug in the Indian subcontinent for Allium sativum contains phosphorus, iron and copper,
over 5000 years. The hepatoprotective effect of A. which have multiple beneficial effects like antimicrobial,
marmelos in alcohol-induced liver injury was evaluated antithrombotic, hypolipidemic, anti-arthritic, antitumor
for biochemical parameters. Many studies have validated and anti-diabetic effects (Sheela et al., 1992). It also
the ethnomedicinal uses and indicated that the fruit contains allyl propyl disulphide, diallyl disulphide and
possesses broad range of therapeutic effects like alliin, which increase hepatic metabolism and insulin
antioxidant, inhibition of lipid peroxidation, release from pancreatic -cell and/or insulin sparing
antibacterial, antiviral, gastroprotective, anti-diarrheal, effect (Bever et al., 1979).
hepatoprotective and anti-diabetic effects. The aqueous Active compound allyl propyl and diallyl sulfide
extract of leaves of A. marmelos has reported to have played a role in decrease blood glucose levels. The
improves digestion and reduces blood sugar and urea, aqueous homogenate orally administered to rabbits
serum cholesterol in alloxanized rats. Instead of significantly increased hepatic glycogen, free amino acid
exhibiting hypoglycemic activity, the extract also content, decreased fasting blood glucose, and triglyceride
prevented blood sugar level at 1h in oral glucose levels in serum (Zacharias et al., 1980).
tolerance test (Karunanayake et al., 1984). Aloe vera and Aloe barbadensis
Allium cepa Aloe vera belong to Aloaceae family, has been
Allium species are among the oldest cultivated used for medicinal purpose from a very long time. Many
crops. Diverse representations in Egyptian artifacts studies worldwide indicated that aloe is a general tonic
dating to 2700 BC suggested that onions had been for the immune system and helps in fighting of all kind
cultivated and in wide use by that time. Many ether illness. Aloe has an important role to play in managing
soluble fractions and insoluble fractions of dried Allium diabetes. Some studies have found that two tablespoons
powder show anti-hyperglycemic activity in the diabetic of aloe decreased blood sugar levels. Extracts of aloe
rabbits. Allium cepa is also known to have antioxidant effectively increased glucose tolerance in normal and
and hypolipidaemic activity. Sulfur containing amino diabetic rats (Shibib et al., 1993). Aloe vera reduced
acid from Allium cepa, S-methyl cysteine sulphoxide hyperglycemia and hypercholesterolemia in diabetic
induced diabetic rats significantly controlled blood patients. Active compound of Aloe vera, aloeres in which
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